In this application we request continuing support for our studies of MED myopathy, a model hereditary and delayed disease of the mouse motor unit that in some ways resembles congenital motor neuron disease syndromes in man including peroneal muscular atrophy and amyotrophic sclerosis. Previous work in our laboratory established the MED gene in the C576J black mouse and morphological studies demonstrated normal structure of neuromuscular junctions and evidence of myofiber degeneration. We have also shown that there are no defects in the overall energy metabolism, electrolyte or nucleic acid content of the affected muscles. Our most recent studies have demonstrated a defect in protein synthesis in the skeletal muscles of homozygous MED mice. Thus far this abnormality can only be demonstrated in vivo. One explanation of this finding is that in vivo, an abnormal "trophic" repressor interferes with protein synthesis. Pilot studies of the effects of MED serum, spinal cord and peripheral nerve extracts on protein synthesis in normal mice were performed with muscles using C14 histidine as a label and we plan to extend these studies to include assays of 3-methyl histidine excretion, a specific breakdown product of myofiber metabolism. The system will be used to follow the action of extracts of spinal cord and peripheral nerves on myofiber protein synthesis in vivo. Other approaches to the question of the influence of trophic substances will be to transplant minced MED anterior tibial muscles into normal and heterozygous MED mice from which this muscle has been excised and observations of the effect of innervation by normal (non-MED) neurons of MED muscle in mixed organ culture. Appropriate histochemical and ultrastructure morphologic studies will be performed in parallel with the biochemical assays. Preliminary pilot experiments indicate that MED myopathy may be a unique instance of a hereditary myopathy caused by gene determined abnormalities of neural "trophic" factors. Such tropic factors may be of importance in dystrophic diseases in man.